Hyperlipidemia is a symptom associated with an abnormal increase in the lipoprotein lipids in blood plasma, and since this symptom is strongly associated with diseases such as arteriosclerosis and myocardial infarction, treatment of the symptom has been considered to be important.
For the treatment of hyperlipidemia, various medicaments such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (hereinafter, may also be referred to as statin), fibrate-based drugs, nicotinic acid, anion-exchange resins, cholesterol absorption inhibitory drugs, probucol, dextran sulfate and ethyl icosapentate have been used, and statins such as pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin and rosuvastatin have taken the leading position in recent therapeutic agents of hyperlipidemia Among the statins, pitavastatin or salts thereof are known to have a potent HMG-CoA reductase inhibitory effect, thus being useful as an agent for lowering the plasma cholesterol concentration (see, Patent Reference 1). However, according to the results of clinical trials, the rate of improvement in the total plasma cholesterol concentration achieved by pravastatin, which is a first generation statin, is 68.6%, while the rate of improvement in the total plasma cholesterol concentration achieved by pitavastatin, which exhibits a strong cholesterol lowering effect, is still the same 93.9%; thus, sufficient improvement in the total cholesterol concentration in blood plasma has not observed in the remaining patients (see, Non-Patent Reference 1).
Yu et al. compared the differences in the effect of drugs in a group of familial hyperlipidemic patients exhibiting resistance to the treatment with a statin, a group of familial hyperlipidemic patients benefiting from the treatment with the same drug, and a group of non-familial hyperlipidemic patients (control group), by utilizing fibroblast cells that have similar properties to hepatic cells. As a result, in the group of familial hyperlipidemic patients benefiting from the treatment with a statin and in the control group, when the cells were brought under the effect of statin, there was an increase in the expression of LDL receptors which have a function of taking up LDL cholesterol from the blood into the liver, along with an increase in the expression of HMG-CoA reductase. On the other hand, in the group of patients exhibiting resistance to the treatment with a statin, the expression of HMG-CoA reductase was increased, but the expression of LDL receptors was not increased. That is, it is proved that one of the mechanisms for the manifestation of resistance to the treatment with a statin is related to the lack of increase in the expression of LDL receptors (see, Non-Patent Reference 2).
It has been reported that a phenomenon similar to the case of the familial hyperlipidemic patients exhibiting resistance to the treatment with a statin, is also observed in rats. In other words, it is a well known fact to those having ordinary skill in the art that statins do not lower the total plasma cholesterol concentration in rats, and the mechanism of such phenomenon has been reported to be based on the observations that (1) even though statins are administered, HMG-CoA reductase is vicariously increased in the liver to maintain cholesterol synthesis, and that (2) in rats, even though statins are administered, LDL receptors are not increased (see, Non-Patent References 3 and 4). Therefore, it is considered that a drug exhibiting an effect of lowering the total plasma cholesterol concentration and the LDL cholesterol level in rat, is also effective in those patients originally exhibiting resistance to the treatment using statins.
Meanwhile, the main components of the lipoprotein lipids in plasma include cholesterol, triglycerides and the like. Since hyperlipidemic patients in many cases have been observed not only to have an increase in the plasma cholesterol concentration, but also to have an increase in the plasma triglyceride concentration, a drug which lowers the plasma triglyceride concentration as well as the plasma cholesterol concentration has been desired. Generally, when statins are administered to hyperlipidemic patients, the plasma cholesterol concentration is sufficiently lowered, but the lowering effect is often insufficient for the plasma triglyceride concentration. However, a method of treating a hyperlipidemic patient having both high plasma cholesterol concentration and high plasma triglyceride concentration, by increasing the dosage of statin for the purpose of lowering both concentrations, has problems in the aspects of safety and the like, and thus has not been recommended.
As the drug for lowering the plasma triglyceride concentration, fibrate-based drugs represented by a fenofibrate are known, and combined use of a statin and a fibrate-based drug has been reported (see, Patent Reference 2, Non-Patent Reference 5). However, combined use of a fibrate-based drug and a statin has been reported to induce the onset of rhabdomyolysis as a side effect, in patients suffering from renal disorders, and thus this combination has been subject to cautious administration.
As another group of drugs for lowering the plasma triglyceride concentration, those created as a result of paying attention to the action of peroxisome proliferators-activated receptor (PPAR) α-activation, which is the operating mechanism for fibrate-based drugs, are known. For example, a phenoxybutyric acid derivative represented by the following formula (1) has been reported to have an effect of lowering the plasma triglyceride concentration, and the derivative is known to be useful for hyperlipidemia, arteriosclerosis, diabetes mellitus, diabetic complications, inflammations, cardiac diseases and the like (see, Patent Reference 3, Non-Patent Reference 6). However, it has not been known of what influence a combination of this phenoxybutyric acid derivative and a statin would exert on the lipids in blood.
Furthermore, diabetes mellitus is a disease having a risk of inducing various characteristic complications, including the “major vascular complications,” that is, ischemic cardiac diseases (angina pectoris, myocardial infarction), cerebral infarction and arteriosclerosis obliterans, as well as diabetic neuropathies, diabetic nephropathy, diabetic retinopathy and the like, as a result of a pathological increase in the blood glucose level caused by abnormal glucose metabolism. As the therapeutic agents for diabetes mellitus, insulin, sulfonylurea drugs (SU drugs), biguanide drugs (BG drugs), α-glucosidase inhibitors (αGI drugs), thiazolidine derivatives (TZD drugs) and the like are known. However, it has not been known of what influence would be exerted by a combination of phenoxybutyric acid derivative and statin, on the blood glucose level.
Furthermore, the metabolic syndrome refers to a state in which resistance to insulin (decrease in the operation of insulin) has been developed because of accumulated visceral fat, and thus risk factors of arteriosclerosis such as abnormal glucose metabolism (abnormal glucose tolerance, diabetes mellitus), abnormal lipid metabolism (hypertriglyceridemia, hypo-HDL-chloesterolemia), and hypertension, converge in one individual. Although each one of the risk factors may be expressed at low degrees, when multiple risk factors are present together, the onset of arteriosclerotic diseases increases synergistically. Thus, the metabolic syndrome has attracted global attention in recent years, as a potent risk factor comparable to high cholesterol level. Various drugs for treating each of the risk factors are being produced, but yet no drug has been approved as a therapeutic agent for metabolic syndrome.    Patent Reference 1: JP-A No. 1-279866    Patent Reference 2: U.S. Pat. No. 6,511,985    Patent Reference 3: WO 2005/023777 pamphlet    Non-Patent Reference 1: J. Olin. Therap. Med., 17, 857-883 (2001)    Non-Patent Reference 2: Atherosclerosis, 124, 103-117 (1996)    Non-Patent Reference 3: J. Lipid. Res., 39, 75-84 (1998)    Non-Patent Reference 4: Biochim. Biophys. Acta, 1254, 7-12 (1995)    Non-Patent Reference 5: Diabetes Care, 25, 1198-1202 (2002)    Non-Patent Reference 6: J. Pharmacol. Sci., 103 suppl. 1, 244P (2007)